Dipepeptidyl peptidase IV inhibitors (DPP-IV inhibitors) are a class of oral hypoglycemic agents that block the enzyme DPP-IV and have been used to treat diabetes mellitus type 2. Saxagliptin has the chemical names (1S,3S,5S)-2-[2(S)-2-amino-2-(3-hydroxy-adamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile or (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile and the structural formula [I]. It is an orally active reversible DPP-IV inhibitor that is the active ingredient in the form of its hydrochloride salt in the ONGLYZA® tablet products originally developed by Bristol-Myers Squibb, and now marketed by AstraZeneca.

Saxagliptin and its hydrochloride and trifluoroacetic acid salts are disclosed in U.S. Pat. No. 6,395,767. U.S. Pat. No. 7,420,079 and U.S. Pat. No. 8,278,462 disclose a process for the preparation of saxagliptin, its hydrochloride salt, trifluoroacetate, and benzoate salts, and saxagliptin monohydrate. U.S. Pat. No. 7,705,033 discloses a process for the preparation of saxagliptin monohydrate. U.S. Pat. No. 7,214,702 discloses a process for the preparation of saxagliptin or its hydrochloride salt.
The above documents disclose a process for the preparation of saxagliptin, which involves condensation of 2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid amide with adamantan-1-yl-tert-butoxycarbonylamino acetic acid.
U.S. Pat. No. 7,186,846 discloses a process for the preparation of saxagliptin which involves reacting 2-aza-bicyclo[3.1.0]hexane-3-carbonitrile with trifluoroacetic acid 3-[carboxy-(2,2,2-trifluoroacetylamino)-methyl]adamantan-1-yl ester, followed by reductive cleavage of protected saxagliptin.
Hiroshi Fukushima et al., “Synthesis and Structure—Activity Relationships of Potent 1-(2-Substituted-aminoacetyl)-4-fluoro-2-cyanopyrrolidine Dipeptidyl Peptidase IV Inhibitors,” Chemical and Pharmaceutical Bulletin, Vol. 56(8), pages 1110-1117 (2008), reports the instability of 2-cyanofluoropyrrolidine derivatives at pH 6-8, due to intramolecular cyclization of basic nitrogen to a cyano group, leading to the formation of cyclic amidine which further transforms to diketopiperazine derivatives. Saxagliptin, being a 2-cyanopyrrolidine derivative, may undergo intramolecular cyclization to form a cyclic amidine.
The above reported processes suffer from the drawback that the tert-butyloxy carbonyl (“BOC”) group is too sensitive in acidic conditions, which exist during the condensation of 2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid amide with adamantan-1-yl-tert-butoxycarbonylamino acetic acid, which leads to formation of unwanted impurities. Further, deprotection of BOC requires harsh and more acidic conditions. Moreover, using BOC as a protecting group makes the reaction monitoring difficult using thin layer chromatography (“TLC”) and tedious since it is less sensitive to ultraviolet (“UV”). BOC also is relatively expensive, making the process not viable industrially.
Indian Application 2065/CHE/2012 discloses a process for the preparation of saxagliptin which involves the use of the benzyloxy carbonyl group (“CBZ”) for protection of the amino group. However, CBZ deprotection would eventually lead to saxagliptin, which by itself is unstable and prone to intramolecular cyclization. Moreover, CBZ is difficult to handle on an industrial scale because of its liquid state and lacrimating properties.
Therefore, there is a need for improved and industrially feasible processes for the preparation of saxagliptin.